Recently, thromboembolic disorders, such as myocardial infarction, cerebral thrombosis and peripheral arteriothrombosis, are increasing year by year with the popularization of Western life-styles and the increase in aged population, and there is much increasing social demand for the treatment of such disorders. Anticoagulant therapy as well as fibrinolysis therapy and antiplatelet therapy is a part of medical therapy for treatment and prevention of thrombosis (Sogo Rinsho, 41: 2141-2145, 1989). In particular, anticoagulants for prevention of thrombosis indispensably require high safety for long-term administration and the ability of surely and appropriately expressing the anticoagulation activity. However, the anticoagulating ability of warfarin potassium, which is only one oral anticoagulant now being popularly used in the world, is difficult to control because of the characteristic of itself based on the action and the mechanism thereof (J. Clinical Pharmacology, 32, 196-209, 1992; and N. Eng. J. Med., 324 (26), 1865-1875, 1991), and the drug is extremely difficult to use in clinics; and the provision of anticoagulants that are more useful and are easier to use is expected.
It is known that thrombin acts to convert fibrinogen into fibrin in the final stage of coagulation, while deeply participating in the activation and the coagulation of platelets (Satoshi Matsuo's T-PA and Pro-UK, Gakusai Kikaku, pp. 5-40, Blood Coagulation, 1986), and its inhibitors have been the center of studies of anticoagulants as the target in drug development for a long period of time.
On the other hand, the activated blood coagulation factor X is an enzyme to produce thrombin that plays a key role of blood coagulation, and as it exists in the junction of intrinsic and extrinsic coagulation cascade reactions, its inhibitors could have a possibility of efficiently inhibiting blood coagulation systems (THROMBOSIS RESEARCH (19), 339-349, 1980). Further, It has been proved that, different from thrombin inhibitors, the activated blood coagulation factor X inhibitor does not have a platelet coagulation inhibiting effect but can specifically inhibit blood coagulation, and that, in a thrombotic model test with animals, it exhibits antithrombotic effect but not exhibiting a side effect of hemorrhage, and the inhibitor is therefor specifically noted (Circulation, 1991, 84, 1741).
As compounds having the ability of inhibiting the activated blood coagulation factor X, known are amidinonaphthylalkylbenzene derivatives or their salts (JP-A 5-208946; Thrombosis Haemostasis, 71 (3), 314-319, 1994; and Thrombosis Haemostasis, 72 (3), 393-396, 1994).
Patent Reference 1 (WO 01/74791) describes diazepane derivatives of the following general formula or their salts, as compounds having the ability of inhibiting the activated blood coagulation factor X. However, they differ from the compounds of the present invention in the structure in point of the presence or absence of diazepane.
(Ring A and ring B: the same or different, each representing an aryl or heteroaryl optionally having from 1 to 3 substituents; and the publication is referred to for the other symbols.)
Patent Reference 2 (WO 02/42270) describes substituted benzene derivatives of the following general formula or their salts, as compounds having the ability of inhibiting the activated blood coagulation factor X. However, they differ from the compounds of the present invention in the structure of the ring B.
(Ring A: benzene ring, or a 5- or 6-membered hetero ring having from 1 to 4, the same or different types of hetero atoms selected from N, S and O. Ring B: when R4 is a hydrogen atom or —SO3H, it is a piperidine ring of which the nitrogen atom is substituted with R7, etc. The publication is referred to for the other symbols.)
Further, Patent Reference 3 (WO 03/26652) describe compounds of a general formula P4—P-M-M4 (M: 3 to 10-membered carbon ring, or 4- to 10-membered hetero ring. P: 5- to 7-membered carbon ring or 5- to 7-membered hetero ring condensed with the ring M, or it is absent. One of P4 and M4 is -Z-A-B, and the other is -G1-G. The publication is referred to for the other symbols.), as compounds having the ability of inhibiting the activated blood coagulation factor X. However, they differ from the compounds of the present invention in the structure of -Z-A-B, etc.    Patent Reference 1: International Publication WO 01/74791    Patent Reference 2: International Publication WO 02/42270    Patent Reference 3: International Publication WO 03/26652